Overview
This lecture reviews thiazide diuretics, focusing on their renal physiology, mechanisms, clinical uses, side effects, and differences among agents.
Kidney Physiology & Diuretic Sites
- The nephron is the functional unit of the kidney, filtering blood and forming urine.
- Proximal renal tubule reabsorbs ~40–60% of sodium and water.
- Thick ascending loop of Henle (loop diuretics site) reabsorbs ~20–40%.
- Distal convoluted tubule (DCT, thiazide site) reabsorbs ~5–10%.
- Collecting duct concentrates urine and reabsorbs free water, minimal sodium reabsorption.
Thiazide Diuretics: Mechanism & Types
- Thiazides block the sodium-chloride co-transporter in the DCT, causing mild diuresis.
- Agents include hydrochlorothiazide (HCTZ), chlorthalidone, indapamide, and metolazone.
- Chlorthalidone also inhibits carbonic anhydrase in the proximal tubule, potentially increasing effectiveness.
Pharmacokinetics & Dosing
- Thiazides must be actively secreted into the renal tubule to work; reduced efficacy in renal impairment.
- Chlorthalidone has the longest half-life and duration of action, offering better 24-hour blood pressure control.
- Indapamide and metolazone are more potent (require lower doses).
- Most thiazides have a ceiling effect; higher doses do not increase efficacy, only side effects.
Clinical Uses & Considerations
- Effective as first-line antihypertensives in most populations, including African-Americans.
- Often used in combination with other blood pressure medications.
- Less effective as kidney function declines (particularly when creatinine clearance <40 mL/min).
- Generally avoided in pregnancy due to reduction in plasma volume.
Side Effects & Monitoring
- Can cause hyponatremia, especially gradual and possibly severe.
- Increase calcium reabsorption, leading to hypercalcemia; may benefit osteoporosis.
- May cause metabolic alkalosis, mild hypokalemia, and increase uric acid (risk of gout).
- Associated with increased blood sugar (hyperglycemia) and slightly higher diabetes risk.
- Risk of orthostasis in the elderly due to volume depletion.
- Sulfa allergy cross-reactivity is low, as thiazides have a different sulfonamide structure than antibiotics.
Key Terms & Definitions
- Nephron — Functional unit of the kidney, responsible for urine formation.
- Distal Convoluted Tubule (DCT) — Nephron segment where thiazide diuretics act.
- Sodium-Chloride Co-Transporter — The target blocked by thiazides in the DCT.
- Hyponatremia — Low blood sodium levels.
- Hypercalcemia — Elevated blood calcium levels.
- Ceiling Effect — Maximum drug effect reached, after which higher doses provide no additional benefit.
Action Items / Next Steps
- Review tables comparing duration, potency, and side effects of thiazide diuretics.
- Understand key differences and indications for each thiazide agent.
- Study mechanisms leading to major side effects, especially electrolyte changes.
- Be able to explain why chlorthalidone may be preferred over HCTZ.